Knock-in of the Wt1 R394W mutation causes MDS and cooperates with Flt3/ITD to drive aggressive myeloid neoplasms in mice.

Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the gene are described in 10-15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar mutations have been reported in adult patients with myelodysplastic syndrome (MDS). mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 () commonly co-occur with -mutant AML, suggesting a cooperative role in leukemogenesis. The functional role of mutations in hematologic malignancies appears to be complex and is not yet fully elucidated. Here, we describe the hematologic phenotype of a knock-in mouse model of a mutation (R394W), described in cases of human leukemia. We show that mice develop MDS which becomes 100% penetrant in a transplant model, exhibit an aberrant expansion of myeloid progenitor cells, and demonstrate enhanced self-renewal of hematopoietic progenitor cells . We crossbred mice with knock-in mice, and show that mice with both mutations ( / ) develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model.